Manufacturing Good Manufacturing Practices (GMP) PDF

Manufacturing (Tue Aug 20) A reliable evidence for GMP (Good Manufacturing Practices) compliance. Quality by design is the only solution to overcome the quality-related complaints in an organization. An essential element of quality assurance is good documentation practices. The system of document...

Manufacturing (Tue Aug 20) A reliable evidence for GMP (Good Manufacturing Practices) compliance. Quality by design is the only solution to overcome the quality-related complaints in an organization. An essential element of quality assurance is good documentation practices. The system of documentation devised or adopted should have as its main objective to establish, monitor, and record "quality" for all aspects of the production, quality control and quality assurance. HOW TO CREATE A GOOD DOCUMENTATION SYSTEM S.O.P. versus W.I. QUALITY PROCEDURE/SOP WORKING INSTRUCTION Process oriented Task oriented Describe step of procedure Describe detail instruction Supporting the Quality Manual Operation guidance Explain general description on certain Dedicated to explain special task, process and give systematic action to method, or technique which should be ensure product quality done to achieve target quality Procedure guideline which involve Instruction guidance which dedicated several departments and/or sections for certain department or section only During implementation need other During implementation can stand alone supported documents Guideline at organization level Guidance at operational level DOCUMENT 1.Document is : A complete history of each batch from starting materials to finished products A record activities for : maintenance storage quality control primary distribution specific matter related to GMP 2.Documents should be designed, prepared, reviewed and distributed with care. 3.All documentation must be organized into files which must be maintained for a specified period of time. 5 years CONTENT OF DOCUMENT What should be written in the document: Name of document Name of company, department or division of the maker Document number Page and number of pages of document Number of revision Date of approved Name and signature of the person who prepared the document Names and signatures of the person who reviewed and person approved the document Body of document Document receiver NUMBERING SYSTEM Every document should have a number from the Control Division. The numbering system should be accomplished for easy retrieval and control of the document. DOCUMENT CORRECTION When a wrong entry on document is made, the following actions must be carried out: Draw a line across the original entry (to preserve original entry) The new entry should be written close to original entry Correction must be initialed & dated computerized : - password pdf :- dedicated person QA DOCUMENT CONTROL Documents should be dated and authorized approved, signed and dated by appropriate authorized persons no document should be changed without authorization All document records should be completed as the process proceeds.  Distribution list of documents should be recorded Obsolete documents should be : taken from users, based on distribution list marked "obsolete", archived Create a list of running documents, centralized. Use only updated documents DISTRIBUTION DOCUMENT Distribution of documents should be the up-to-date documents. Copy of documents should be distributed to relevant parties Document Data Control Division or QC can distribute the document Main document should be received by Production and Quality Control Department Supporting document is distributed to related division only REVISION & RENEWAL Should be made periodically, or if needed Obsolete documents should be retrieved from all: relevant parties and its original copy should be archived The date of revision should be stated in the new documents Every revision should be approved by authorized person RECORD KEEPING RULES "Do Not" Rules DO NOT scribble out mistakes (obscures entry) DO NOT write correct entries over incorrect entries (writing over obscures original entries) DO NOT forget to enter all required info DO NOT forget to initial and write date of entry / DO NOT use colored ink/pencil DO NOT leave mistakes uncorrected (check your entries) BATCH PROCESSING RECORD Should be prepared for each batch of product. Each Batch Processing Record should include the following : name of product batch or code number batch formula brief processing process  processing date and yield identity of individual major equipment & lines or location used records of cleaning of equipment used for processing as appropriate in-process control and laboratory results, such as pH and temperature test records any sampling performed during various steps of processing any investigation of specific failure or discrepancies results of examinations on bulk products Active Pharmaceutical Ingredient (API) Drug Supplier A component designed to provide pharmacological Includes manufacturers, importers, and traders of effects to the human or animal body. drugs. Batch Drug Trader A defined quantity of a drug or material, produced A registered drug product owner who sources in a single manufacturing cycle, with uniform materials, provides production standards, and character and quality within specified limits. subcontracts manufacturing to a licensed manufacturer, while also handling distribution and Batch/Lot/Control Number marketing. A unique identifier that traces the complete history of a drug product's manufacture, processing, Excipient packaging, storage, and distribution. Any component besides the active ingredient that ensures the drug or API is effectively administered Batch Size and achieves optimal therapeutic effects. It should The number of dosage units produced in a batch. be safe in the amounts used, minimal, and not affect the drug's bioavailability, efficacy, or testing. Departments in a Drug Establishment Marketing Lot Research A batch or a portion of a batch with uniform quality Production within limits and a unique lot number. QA/QC Engineering Master Record (Master Formula) Purchasing Records containing the formulation, specifications, Medical manufacturing procedures, quality assurance requirements, and labeling of a finished product. Drug Articles intended for diagnosis, cure, treatment, or Pharmaceutical Preparations (Pharmaceuticals) prevention of disease, or to affect body Means of administering drugs as formulated structure/function in humans or animals, including preparations; dosage forms with active components of such articles, as recognized by a pharmaceutical ingredient(s) (API) and excipient(s). compendia monograph. Theoretical Yield Drug Establishments The quantity that should be produced after the Manufacturer whole manufacturing process in the absence of any Importer loss or error in the actual production. Trader Supplier Drug Importer An establishment that imports raw materials, active ingredients, or finished products for its distribution or wholesale to other establishments or outlets. Drug Manufacturing The creation of any drug article, including its packaging, repackaging, labeling, and any testing or control procedures applied during its production and distribution.  Guidelines or rule Step by step Documentation procedure General Principles Standard Operating Procedures (SOPs) Documents should be: Which activities require SOPs? Designed, prepared, reviewed, and Batch release or rejection (+ receipt). distributed with care. Maintenance of distribution records. Purpose of documentation: Equipment assembly and validation. Ensure that all materials, manufacturing Calibration and operation of analytical methods, quality control, personnel apparatus. responsibilities, and release procedures are Personnel recruitment, training, clothing, specified, communicated, and authorized. and hygiene. Provide audit trail. Environmental monitoring. Distribution of documentation: Internal labeling, quarantine, and storage of Electronically or photographically recorded materials. data. Sampling of materials. Types of Documentation Batch numbering systems. Labels, specifications, and master formulae. Batch processing and batch packaging Batch Processing Records Identification of a product records. Name of the product, batch number. Standard operating procedures. Dates and times for major steps in the Stock control and distribution records. process. Water quality manual. Name of personnel responsible for each stage of production (check signatures). Theoretical quantities for materials in the batch. Reference number and quantity of materials used in the batch. In-process controls carried out, and results obtained. Yield at each stage with comments on deviations. Area clearance check, instructions to operators. Record of activities. Batch Packaging Records Records of the Products that make Details of packaging operation, including equipment and line used. Store returns. Comments on deviations from the process and actions taken. Area clearance check. Product variables. Record of activities and check signatures. Batch number, theoretical quantity, and actual quantity of finished product. Reconciliation calculations, dates, and times of operation. Name of person responsible for packaging, initials of operators carrying out each step. Job Description Packing Instructions Supervisor Special precautions, including area Assign batch number. clearance checks. Accomplish Batch Manufacturing Record Description of the packaging operation. (BMR). In-process control checks, with sampling May assign individuals or groups to assist instructions and acceptance criteria. others if needed. Production Ensure that apparatus or equipment is ready for use. Accomplish pertinent portions of the PBR and affix signatures and dates on it. Perform IPQC together with Quality Control. Record the time started and finished performing certain operations. Quality Control Ensure that everyone is following GMP. Ensure documents are accomplished completely. Ensure the working area and surfaces are clean. Perform the required in-process and finished product quality control tests. Inspect equipment and validate processes. Prepare, accomplish, and submit QC reports to the supervisor. Keep retention samples. Packaging and Labeling Prepare Packaging Instructions according to SOP. Ensure all packaging requirements and specifications are met. Clean all packaging materials. Accomplish Packaging and Labeling Record. Check that the correct batch or lot number, manufacturing date, and expiration date are stamped on the correct label. Maintenance Prepare the working area before and after production. Check the voltage of the equipment before plugging it, and unplug after use. Dispensing Check and accomplish documents of materials (PBR). Weigh, measure, and check the amounts of materials needed. Return the requested material properly. Good Manufacturing Practices (GMP) Processing date and yield. Numbering System Identity of individual major Every document should have a number from equipment & lines or location the Control Division. used. The numbering system should be Records of cleaning of accomplished for easy retrieval and control equipment used for of the document. processing as appropriate. Distribution Document In-process control and The distribution of documents should be laboratory results, such as pH up-to-date documents. and temperature test Document Data Control Division or QC can records. distribute the document. Any sampling is performed The main document should be received by during various steps of the Production and Quality Control processing. Department. Any investigation of specific Supporting documents are distributed to failures or discrepancies. related divisions only. Results of examinations on Record Keeping Rules bulk products. DO NOT scribble out mistakes (obscures Quality Control Record entry). Record for each testing, assay result, and DO NOT write correct entries over incorrect release or rejection of starting materials, entries (writing over obscures original intermediates, bulk, and finished product entries). should be maintained. DO NOT forget to enter all required info. ➔ QC record may consist of: DO NOT forget to initial and write the date Date of test. of entry. Identification of the material. DO NOT use colored ink/pencil. Supplier name. DO NOT leave mistakes uncorrected (check Date of receipt. your entries). Original batch number if any. Document Control Batch number. Documents should be dated and authorized. Quality control number. All document records should be completed Quantity received. as the process proceeds. Date of sampling. A distribution list of documents should be Quality control results. recorded. Document Correction Create a list of running documents, When a wrong entry on the document is centralized. made, the following actions must be carried Obsolete documents should be: out: ➔ Taken from users, based on the ➔ Draw a line across the original entry distribution list. (to preserve the original entry). ➔ Marked "obsolete", archived. ➔ The new entry should be written Batch Processing Record close to the original entry. Should be prepared for each batch of ➔ Correction must be initialed & dated. product. ➔ Computerized: password, dedicated ➔ Each Batch Processing Record person. should include: Content of Document Name of product. What should be written in the document: Batch or code number. ➔ Name of document. Batch formula. ➔ Name of company, department, or Brief processing process. division of the maker.  ➔ Document number. SOP vs. WI ➔ Page and number of pages of the document. Quality Working Instruction ➔ The number of revisions. Procedure/SOP ➔ Date of approval. ➔ Name and signature of the person Process-oriented Task-oriented who prepared the document. Describe the step of Describe detailed ➔ Names and signatures of the person the procedure. instructions. who reviewed and person approved the document. Supporting the Quality Operation Guidance ➔ Body of document. Manual ➔ Document receiver. Explain general Dedicated to Revision and Renewal descriptions of certain explaining special Should be made periodically, or if needed. processes and give tasks, methods, or Obsolete documents should be retrieved systematic action to techniques that should from all relevant parties and their original ensure product quality. be done to achieve copy should be archived. target quality. The date of revision should be stated in the Procedure guidelines Instruction guidance new documents. that involve several which dedicated to Every revision should be approved by an departments and/or certain departments or authorized person. sections. sections only. Other Documents Qualifications, job descriptions, duties & During implementation During implementation responsibilities. need other supported can stand alone. documents. Training (schedule, program & evaluation). SOPs. Guideline at the Guidance at an Stock control & distribution records. organization level. operational level. Preventive Maintenance. Pest control records. Cleaning records. General Documentation Principles Document is: ➔ A complete history of each batch from starting materials to finished products. ➔ A record of activities for: a. Maintenance b. Storage c. Quality Control d. Primary Distribution ➔ The specific matter related to GMP. Documents should be designed, prepared, reviewed, and distributed with care. All documentation must be organized into files which must be maintained for a specified time. Quality Management Sanitation and Hygiene Basic Requirements for GMP-1 (WHO) Special areas might require additional or Clearly defined and systematically reviewed separate lab attire. processes. Smoking, eating, and drinking are not Qualification and validation are performed. allowed in production areas, laboratories, Appropriate resources are provided. and warehouses. Good Manufacturing Practices (GMP) Chewing gums, and keeping food or drinks Part of QA that ensures products are are not allowed. consistently produced and controlled. No plants within the premises. Aim: Refreshment and rest areas including - diminishing risks that cannot be comfort rooms should be on the other side controlled by testing the product. of changing rooms and should be Quality Management System separated. The assembly of all planned and systematic Personnel actions is needed to provide adequate Health Examination confidence that a product, process, or Personal Hygiene service will satisfy given quality Training and Seminars requirements. Premises Principles of Quality Assurance (QA) Design of the premises. ➔ Covers matters regarding the quality Avoidance of build-up of dirt and dust. of a product. Cleaning SOP and records. ➔ GMP is under Quality Assurance. Equipment and Materials Quality Control (QC) Cleaning and decontamination. ➔ Operational techniques and Proper selection of disinfectants and activities used to satisfy quality cleaners. requirements. Test for residues. ➔ Aims to detect and correct problems. Quality Management System Requirements ➔ WHO framework of 12 building blocks, called quality system Self-Inspection and Quality Audits essentials (QSES). Procedures are documented. Consists of an effective follow-up program. Items for Self-Inspection (WHO). ➔ Written instructions provide a minimum and uniform standard. ➔ Covering all aspects of GMP. Self-inspection and Quality Audits. ➔ To be done at specific time points every year. ➔ Also on special cases such as recalls, repeated failures, or upon order of FDA. ➔ Should consist of personnel that can act objectively, have no conflict of interest, and have experience as an observer of a self-inspection team before becoming a team member. Personnel ➔ Has order and proper designation of Importance materials and products. The establishment and maintenance of a ➔ Separated and segregated starting satisfactory system of QA, manufacture, materials, intermediate products, and control of drug products relies on and finished products. people. ➔ Temperature and relative humidity Principle: are controlled. ➔ There must be sufficient qualified personnel to carry out tasks. Personnel Requirements Adequate number Advance of Cross-Contamination With necessary qualifications Segregated Areas With practical experience Penicillins manufacture. Individual responsibilities should not be so Live bacteria/vaccines. overwhelming that they may present a risk Other biological materials. to the quality of drug products. Ventilation Systems and Airlocks Personnel Training HVAC system. Heating, Ventilation, Air Training in accordance with an approved Airlocks. Conditioning training program. Pressure difference. Continuing training on different aspects Closed Processing Systems relevant to personnel's line of duty. Water/tank system. Training records are kept. CIP Practical training is checked. Clothing Training before undertaking new tasks. Protection of the operator and product. Special training for special tasks such as Special protective gear for highly potent personnel dealing with hazardous products. chemicals. One product one clothing, no interchanging. Premises, Equipment, and Materials Location and Installation Countries Name of Regulatory Avoid congestion or overcrowding Agencies Easily identified With proper order and arrangement Philippines US Food and Drug Accessible during the process of operation. Administration Equipment Philippines (FDA) Equipment must be located, designed, United States of US Food and Drug constructed, installed, and maintained to America Administration (USFDA) suit the manufacturing plant, the products to be manufactured, and the operations to European Union European Medicines be carried out. Agency (EMA) Design Principle Japan Pharmaceuticals and ➔ Material Flow Medical Devices ➔ People Flow Agency (PMDA) ➔ Product Flow Materials Australia Therapeutic Goods Administration (TGA) Storage Areas ➔ Sufficient space. United Kingdom Medicines and  Healthcare Products Regulatory Agency (MHRA) Taiwan Food and Drug Administration, Taiwan (TFDA) Singapore Health Sciences Authority (HSA) Malaysia Drug Control Agency (DCA), China National Medical Products Administration (NMPA) India Drug Controller General of India (DCGI) Thailand Thai Food and Drug Administration (TFDA) Codes Description PIC(s) Guides to GMP EU USAFDA CFRs 210 & 211 & 820 ISO 13485 Medical devices, MDSAP, SS620 ISO 22716 Production, control, storage and shipment of cosmetic products. EXCIPACT GMP & GDP Certification API ICH Q7A WHO GMP Guidelines UNIT OPERATIONS IN PHARMACEUTICAL MANUFACTURING Size Reduction Process of reducing larger size solid unit masses to smaller size unit masses by mechanical means Reasons to reduce particle size:  aid in processing of solid particles by facilitating powder mixing  Improve pharmacological performance of drug  Improve transportation efficiency by reducing bulk volume Principal Means of Size Reduction:  Cutting or shearing  Compressing  Impaction  Attrition  Combined impaction and attrition Factors in choosing a mill: 1. Properties of feedstock 2. Specification of product EXAMPLES OF MILL Mill Feedstock Type Action Product Size Cutter Mill Fibrous, wet mass, dry Cutting and attrition 4-80 mesh powder Hammer Mill Brittle and dry Impact and some 10-325 mesh attrition Ball or rod mill Moderately hard and Attrition and impaction 5-100 micrometers abrasive Hand screen Raw material wet and Shear and attrition dry granulation Oscillating granulator Raw material wet and Attrition and shear 10-50 mesh dry granulation Mortar and pestle Compression Fluid energy mill Moderately hard Attrition and impaction 5-30 mesh Granulation Process by which smaller particles are made to adhere to form larger particles Reasons for granulation:  Prevent segregation of constituents in powder mix  Improve the flow properties of the powder mix because particles are larger and more isodiametric   Improve compression characteristics of mix Methods of Granulation  Wet granulation  Dry granulation  Hot melt granulation Wet Granulation "Wet massing" Massing of the powder mix using a solvent (alone or within a granulating agent) Solvents Used 1. Water - Nonflammable, nontoxic - Hydrolysis - Long drying time 2. Organic solvents - Alternative to dry granulation - For water-sensitive drugs - Rapid drying Examples of Wet Granulation Equipment  Shear granulator  Fluid bed granulator  Spray dryer  Spheronizer/pelletizer Granulators Dry Granulation Particles are aggregated using high pressure For drugs which do not compress well after wet granulation and are sensitive to moisture 2 processes:  Slugging  Roller Compaction Mixing Process of putting together in one mass with more or less thorough diffusion Blending Classification of Mixing Equipment  Batch type - Rotation of the entire mixer body with no agitator  Barrel Mixer  Cube mixer - Rotation of the entire mixer with rotating agitator   V-blender  Double cone mixer  Slanted Double cone - Stationary body with rotating agitator  Ribbon  Sigma blade  Planetary - Stationary body with a rotating mixing blade and high-speed agitator  Barrel  Bowl - Stationary body with moving air as agitator  Fluid Bed Drier  Fluid Bed Granulator  - Continuous type  Zigzag Drying Process of removing water (or other liquid) from a solid or semisolid mass by evaporative process Factors in Choosing a Drying Equipment:  Nature of product  Cost Examples of Drying Equipment:  Tray dryer  Vacuum dryer  Infrared dryer  Radiofrequency dryer  Fluid bed dryer MANUFACTURING SOLID DRUG DELIVERY SYSTEM TABLE 2: Types of Solid Dosage Form Formulation Type Description Immediate-release Intended to release the drug immediately after administration tablet/capsule Delayed-release Drug is not released until a physical event has occurred, e.g., change in tablet/capsule pH Sustained-release Drug is released slowly over extended time tablet/capsule Soluble tablets Tablet is dissolved in water prior to administration Dispersible tablet Tablet is added to water to form a suspension prior to administration Effervescent tablet Tablet is added to water, releasing carbon dioxide to form a effervescent solution Chewable tablet Tablet is chewed and swallowed Chewable gum Formulation is chewed and removed from the mouth after a directed time Buccal and sublingual Tablet is placed in the oral cavity for local or systemic action tablets Orally disintegrating tablet Tablet dissolves or disintegrates in the mouth without the need for water Lozenge Slowly dissolving tablet designed to be sucked Pastille Tablet comprising gelatin and glycerine designed to dissolve slowly in the mouth Hard gelatin capsule Two-piece capsule shell that can be filled with powder, granulate, semisolid or liquid Soft gelatin capsule (softgel) One-piece capsule containing a liquid or semisolid fill SOLID DOSAGE FORMS - POWDERS, GRANULES and PELLETS - CAPSULES - TABLETS Solid Dosage Form Excipients 1. Diluents 2. Binders 3. Lubricants 4. Glidants and Antiadherents 5. Disintegrants 6. Superdisintegrants 7. Added Functionality Ingredients 8. Colorants Diluents An inert substance is frequently added to increase the bulk of a tablet for processing and handling. The lower weight limit for formulation of a tablet is usually 50 mg. Ideally, diluents should be chemically inert, nonhygroscopic, and hydrophilic. Having an acceptable taste is important for oral formulations, and cost is always a significant factor in excipient selection. 1. Lactose 2. Starch 3. Sucrose 4. Mannitol 5. Sorbitol 6. Microcrystalline cellulose 7. Hydrolyzed starch Binder promote cohesiveness within powders, thereby ensuring that the tablet remains intact after compression as well as improving the flow by forming granules impart adequate cohesion without retarding disintegration or dissolution can be added either as a solution or as a dry powder. 1. Water 2. Alcohol 3. Starch Paste 4. Acacia Mucilage 5. Gelatin Solution 6. Tragacanth Mucilage 7. Sucrose Solution 8. Methylcellulose Solution 9. Sodium CMC Solution 10. PVP Solution 11. Sorbitol Lubricant reduce friction between the tablet and the die wall during compression and ejection The best lubricants are those with low shear strength but strong cohesive tendencies perpendicular to the line of shear Glidants and Antiadherents glidants are fine powders and may be required for tablet compression at high production speeds to improve the flow properties of the material into the die or during initial compression stages They are added in the dry state immediately prior to compression and, by virtue of their low adhesive potential, reduce the friction between particles Antiadherents can also be added to a formulation that is especially prone to sticking to the die surface (or picking) Disintegrant added to a formulation to overcome the cohesive strength imparted during compression, thus facilitating break up of the formulation in the body and increasing the surface area for dissolution. They can be either intragranular, extragranular, or both Mechanism of Action: - Swelling - Porosity and Capillary Action (Wicking) - Deformation 1. Starch 2. Starch derivatives 3. Gums 4. Cellulose derivatives 5. MCC (Avicel) 6. Alginates 7. Clays 8. Effervescent mixtures 9. Enzymes Superdisintegrant so called because of the relatively low levels required (2-4% w/w) 3 SUPERDISINTEGRANTS: 1. Sodium starch glycollate (Primojel, Explotab) 2. Crospovidone 3. Croscarmellose sodium 1. Sodium starch glycollate (Primojel, Explotab) - modified starch - made by cross-linking potato starch - can swell up to 12-fold in less than 30 s 2. Crospovidone - cross-linked povidone - completely insoluble in water - rapidly disperses and swells in water, but does not gel even after prolonged exposure - It rapidly exhibits high capillary activity and pronounced hydration capacity 3. Croscarmellose sodium - modified cellulose - a cross-linked polymer of carboxymethyl cellulose sodium - insoluble in water - rapidly swells to 4-8 times its original volume on contact with water QUIZ - SELECT THE BEST ANSWER MATCHING TYPE 1. Starch A. Binder 2. Crospovidone B. Disintegrant 3. MCC C. Diluent 4. Lactose D. Lubricant 5. Starch Paste E. Superdisintegrant 6. Smaller particle adhere to form larger particles F. Drying 7. Large Particles to small particles is achieved by G. Batch type 8. Removal of Water through the process of H. Granulation evaporation 9. A General type of Mixing procedure I. Size Reduction 10. Magnesium Stearate J. Fluid Bed Granulator Added Functionality Excipients description of excipients from inactive ingredients is shifting toward functionally active materials improved versions of long-existing excipients New single-component and coprocessed products have been introduced advances in the understanding of how such substances act and hence how they can be optimally designed Adsorbents Capable of holding moisture in dry state Examples: 1. Silicon dioxide 2. Magnesium carbonate 3. Magnesium oxide 4. Bentonite 5. Kaolin 6. Magnesium aluminum silicate 7. Tricalcium phosphate Wetting Agents Decrease the interfacial tension between the dosage form and the body fluids Surfactants (SURFace ACTive AgeNTS) Examples: 1. Anionic Most common type of surfactant used in drug formulation 2. Non-inonic surfactants that have polar head groups that are not electrically charged 3. Amphoteric have a dual charge on their hydrophilic end, both positive and negative. Sweeteners - Lactose - Sucrose - Sorbitol Mannitol - Dextrose Saccharin Aspartame Use of sweetener in the formulation To mask bitter taste Colorants Increase aesthetic value mask color changes in the formulation and are used to provide uniqueness and identity to a commercial product Division 1. Water Insoluble Pigments  provide opacity to tablet coatings or gelatin shells  can promote stability of light-sensitive active materials  Ex. oxides, titanium dioxide, and some of the aluminum lakes 2. Water Soluble Dyes  usually incorporated within the granulation process  ensure even distribution throughout the formulation   water-soluble dyes can also be adsorbed into a carrier such as starch or lactose and dry blended prior to the final mix Division *Lakes - largely water - insoluble forms of common synthetic water- soluble dyes - prepared by adsorbing the sodium or potassium salt of a dye onto a very - fine substrate of hydrated alumina, followed by treatment with a further soluble aluminum salt - frequently used in coloring tablet coatings - more stable and have greater opacity than a water-soluble dye Synthetic (Dyes) Natural (Pigments) Erythrosine (FDC Red No. 3) Bixin Allura Red (FDC Red No. 40) Anthocyanin Tartrazine (FDC Yellow No. 5) Betacarotene Sunset Yellow (FDC Yellow No. 6) Titanium dioxide Brilliant Blue (FDC Blue No. 1) Iron oxides Fast Green (FDC Green No. 3) Turmeric Indigotine (FDC Blue No. 2) Carminic acid Riboflavin Saffron TABLE 3 Excipients Used in Solid Dose Formulations Excipient Category Examples Fillers/diluents Lactose, sucrose, glucose, microcrystalline cellulose Binders Polyvinyl pyrrolidone, starch, gelatin, cellulose derivatives Lubricants Magnesium stearate, stearic acid, polyethylene glycol, sodium chloride Glidants Fine silica, talc, magnesium stearate Antiadherents Talc, cornstarch, sodium dodecylsulfate Disintegrants and superdisintegrants Starch, sodium starch glycollate, cross-linked polyvinyl pyrrolidone Colorants Iron oxide, natural pigments Flavor modifiers Mannitol, aspartame Powders, Granules, Pellets POWDERS intimate mixtures of dry, finely divided drugs and or chemicals that may be intented for internal or external use Types: - Divided powders - Bulk powders 1. Oral Powders 2. Dentrifices 3. Douche Powders 4. Dusting Powders 5. Insufflations 6. Triturations 7. Aerosols Types of Papers 1. White Bond Paper 2. Glassine Paper 3. Vegetable Parchment 4. Waxed Paper POWDERS REMEMBER!!! - Hygroscopic - absorbs moisture, but does not dissolve - Deliquescent - absorbs moisture and eventually dissolves - Efflorescent - releases water of crystallization - Effervescent - releases carbon dioxide gas in water Principal Means of Milling 1. cutting/shearing 2. compressing 3. rolling 4. attrition 5. impact Blending/Mixing of Powders 1. spatulation 2. trituration 3. geometric dilution 4. sifting 5. tumbling ADVANTAGE DISADVANTAGE - Increased stability - Inconvenient to carry  - Convenience when dispensing drugs - Problems in masking unpleasant with a large dose tastes - Faster dissolution rate - Not for drugs with a low dose - Not for drugs inactivated in the stomach GRANULES aggregates of powders that adhere or bond to each other to form larger unit particles Fines - Act as bridges to fill interparticulate spaces in between granules Qualities of a Good Granulation: 1. Spherical as possible 2. Distribution must resemble bell-shaped curve 3. Uniform in content Essential Properties of Granules for Tablet Production 1. Fluidity 2. Compressibility Flow Characterization: 1. Indirect Methods  Angle of repose  Shear cell determination  Bulk density measurement  Critical orifice diameter 2. Direct Methods  Hopper flow rate  Recording flow meter Problem in Fluidity/Flow ability Improvement of Flowability 1. Alteration of particle size and size distribution - Use of coarser particles - Reduction of the fine particle fraction 2. Alteration of particle shape or texture - More spherical more flowable - Smooth surfaced particles flow better 3. Alteration of surface forces - Reduction of electrostatic charges - Reduction of moisture content 4. Use of flow activators - Use of glidants, lubricants, antiadherents Talc Reducing or altering electrostatic Cornstarch interactions Magnesium stearate Colloidal silicon dioxide Reduce bulk density but may cause flooding Magnesium oxide Disrupt continuous film of adsorbed water surrounding moist particles Silicone-coated talc and sodium bicarbonate Improve flowability of moist or hygroscopic powders 5. Alteration of process conditions Effervescent Granules Methods: 1. Fusion to release water of crystallization of ingredients 2. Addition of moistening binding agent water in alcohol Capsules Size Volume (mL) Fill weight (g) 000 1.37 1.096 Hard Shell Capsules 00 0.95 0.760 0 0.68 0544  Solid dosage form in which one or more medicinal 1 0.50 0.400 and/or inert substances are enclosed within small 2 0.37 0.296 edible shell or container generally prepared from a 3 0.30 0.240 suitable form of gelatin to produce a unit dose, 4 0.21 0.168 mainly for oral use. 5 0.13 0.104  Hard Gelatin Capsule, Starch Capsule, Vegetel, * Assumes a powder density of 0.8g.cm3 HPMC Steps involved in making empty gelatin capsules  Capsule shell components: gelatin, water, sugar, colorants, 0.15% sulfur dioxide, titanium dioxide 1. Dipping 2. Spinning 3. Drying 4. Stripping 5. Trimming and Joining 6. Polishing Gelatin USP - made from partial hydrolysis of collagen obtained from the skin, white connective tissue and bones of animals Components of a Hard Shell Capsule 1. API 2. Bulking Agents 3. Flow Activators/Anti-frictional Agents 4. Disintegrants 5. Surfactants Shells are manufactured in a separate operation from the filling process. Composed of a body and a cap 1. Tapered rim 2. Groove 3. Indentations Dipping:  Pairs of the stainless steel pins are dipped into the dipping solution to simultaneously form the caps and bodies.  The dipping solution is maintained at a temperature of about 50°C in a heated, jacketed dipping pan. Spinning: The pins are rotated to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the capsule ends. Capsule Shells  Size: Made in 8 sizes with 0-4 as the popular sizes  Moisture Content: 15-18% w/w  below 13% will result in problems in capsule filling machinery Trimming and joining  Storage: 21-25C and 35-50% RH  The stripped cap and body portions are trimmed to TABLE 5 Capsule Size and Corresponding Volume or the required length by stationary knives. Weight of Fill  After trimming to the right length, the cap and body portion are joined and ejected from the machine. Methods of Filling Hard Shell Capsule 1. Stroking-in or Dribbling-in 2. Auger or Spindle Dosing Injection wedge 3. Tamping and Disc Dosing Heats the web to gel Delivers metered temperature and injects and 4. Tube Dosing, Intermittent Capsule Filling and the fill material into the web to cause the synchronized fill material to the Closing material to fill the cavities in the die rolls. injection wedge. Hard Gelatin Capsule Shell Filling Applies lubricant to both sides of  The filling material must be compatible with the the web for encapsulation. gelatin shell and, therefore, deliquescent or Casts molten hygroscopic materials cannot be used. gel into a thin  web via Due the moisture content in the capsule shells, they gravity. cannot be used for moisture-sensitive drugs.  All ingredients need to be free of even trace amounts of formaldehyde to minimize cross-linking of gelatin (gelatin will not dissolve!!!). Stores fill material (transfer tank not shown). Soft Shell Capsules Individual capsules are formed, sealed, and cut by Softgels cavities, and tips cut into the perimeter.  Formed, filled and sealed in a single operation  Filled with pumpable solutions or suspension of Removes any capsules remaining in the die rolls. drugs in liquid which will not solubilize the shell  Also pasty materials and dry powders Removes any capsules remaining in the web. Soft Shell Capsules  gelatin, plasticizer, and water (30-40% wet gel)  fill can be a solution or suspension, liquid, or semisolid.  May be shaped as oblong, oval, spherical, tube, suppository type, pearl Cools and solidifies cast gelatin web (chiller Soft shells not shown)  size of a softgel represents its nominal capacity in Aids in curing minims web for  encapsulation Major plasticizer: glycerol (or glycerin)  Alternative plasticizer: Propylene glycol and sorbitol Other excipients are dyes, pigments, preservatives. Transfers delicate softgels for finishing and flavors  Up to 5% sugar can be added to give a chewable quality. Adjusts web tension and pulls netting through machine for discard or optional recycling  Advantages:  improved bioavailability (drug is presented in a solubilized form)  enhanced drug stability  improve patient compliance (ease of swallowing, convenience, and taste) product differentiation via color, shape, and 1. size and product line extension The glycerol-gelatin solution is heated and pumped  can be enteric coated for delayed release onto two chilled drums to form two separate ribbons (usually 0.02-0.04 in. thick) which form each SOLID DOSAGE FORMS half of the softgel. Tablets Solid dosage forms that may or may not contain medicinal substances with or without diluents and prepared either by compression or by molding popular dosage form due to their: 1. simplicity and economy of manufacture 2. The 2. relative stability ribbons are lubricated and fed into the filling 3. convenience in packaging, shipping, and storage machine, forcing the gelatin to adopt the contours Types of Tablets of the die.  Standard and Compressed Tablets  Multiple Compressed Tablets  Sugar-coated Tablets  Film-coated Tablets  Modified-release Tablets  Extended-Release Tablets  Delayed-Release Tablets  Buccal Tablets 3. The fill is  Sublingual Tablets manufactured in a separate process and pumped in,  Chewable Tablets and the softgels are sealed by the application of  Effervescent Tablets heat and pressure.  Hypodermic Tablets Tablet Triturate  Dispensing Tablet Implants or Pellets  Transmucosal Tablets Attributes of a Well-Made Compressed Tablet 1. Ability to withstand the rigors of production, packaging, shipments and dispensing 2. Freedom from defects such as cracks, chipped edges, discoloration and contamination 3. Reasonable chemical and physical stability during 4. Once average storage conditions cut from the ribbon, they are tumble-dried and 4. Ability to release the medicament in a reproducible conditioned at 20% relative humidity. and predicted manner Components of a Tablet pressure control 1. API cam 2. Diluent/bulking agent 3. Binder Hopper 3. Disintegrant upper punch 4. Anti-frictional Agents Feed Shoe die table 5. Colorant discharge chute 6. Flavor/Sweetener upper adjustment collar 7. Adsorbent weight adjustment collar 8. Surfactant Methods of Tablet Manufacture Direct Compression Dry Wet Roller Granulation Granulation Compaction 1. Dispensing 1. Dispensing 1. Dispensing 1. Dispensing 2. Milling 2. Milling 2. Milling 2. Blending 3. Mixing 3. Mixing 3. Preparation 3. Intragranular 4. Tabletting 4. Slugging of binder lubrication 5. Screening 4. Wet mixing 4. Roller slugs 5. Wet compaction 6. Mixing with Screening 5. Milling and disintegrant 6. Drying of screening Tablets are often coated to: 7. Addition of moist 6. Extragranular lubricant granules binder - protect the drug from the external environment 8. Tabletting 7. Dry 7. Extragranular - Provide desired release pattern of API screening lubrication - Mask bitter tastes 8. Addition of 8. Tabletting - increase mechanical strength lubricant - enhance ease of swallowing 9. Tabletting A coating can also be used for: Parts of a Tablet Press - aesthetic or commercial purposes - improving product appearance - identity Parts: Sugar Coated Tablets - A-hopper (stores material for compression) B-feed shoe (delivers and distributes) - beneficial in masking taste, odors, and colors - C-weight adjustment collar - useful in protecting against oxidation - D-upper punch (compact material within die) - once very common due to its aesthetic results and - E-pressure control cheapness of materials - F- die table (die-control shape of tablet) G-discharge - Use has declined in recent years due to the chute complexity of the process and skills required - H-cam (guides the punches) 1- upper adjustment - Tablet weight increase up to 50% collar Typical excipients : - Sucrose (although this can be substituted with low- calorie alternatives) - Fillers - Flavors - film formers - colorants - surfactants Sealing - Waterproofing - Separate core from water (shellac or cellulose acetate phtalate) Subcoating - Round off and contour the tablet - Improve bond between seal coat and sugar coat - Uses gum and sucrose solution Steps: Smoothing 1. preliminary compression step to produce soft tablet - Syruping core 2. Tablet core is placed in a large die containing - To complete the rounding off using 70%w/v sucrose coating material solution 2. Further coating material is added and the content - Substeps: grossing, heavy syruping, regularsyruping compressed - Allowed to dry every after coating 3. A similar light compression is used for the Finishing production of layers 4. A final main compression step used to bind the - Tablet Coating layers together - To attain final smoothness - Jogging - rapid on-off switching of the pan Polishing - Attain sheen/gloss Tablet Coating Compression Coating and Layered Tablets Categories of Tablet Coating - A coating can be applied by compression using specially designed tablet presses 1. Sugar-coating 2. Compression coating process is used when: 3. Film-coating 1. physical separation of ingredients is desired due to 4. Tablet wrapping or Enrobing incompatibility Film-Coated Tablets 2. produce a repeat - action product 3. provide an immediate and a slow-release - Film coating applied to tablets AND capsules component - Process of placing a thin, skin-tight coating of a plastic-like material over a tablet core Release rates can be controlled by: Advantages (over Sugar-coating) - modification of the geometry - composition of the core - weight gain is significantly less (typically up to 5%) - - inclusion of a membrane layer - more resistant to abrasion - less processing time - may be reworked - easier to automate - has capacity to include organic solvents if required - - ideal for tablets with depressed or raised monograms Typical excipients (Non-Aqueous Film Coating):  Cause: low molecular weight plasticizers included in coating formulation  Film former (smooth thin films, cellulose acetate  Remedy: decrease plasticizer concentration and phpthalate) increase molecular weight of plasticizer  Alloying substance (water solubility & permeability, polyethylene glycol) Plasticizer (produce flexibility Cracking and elasticity to the coat, castor oil) Surfactant  Films crack or split (enhance spreadability of coat, polyoxyethylene sorbitan) - Opacifier and colorant (enhance  Cause: high internal stress in film (more than the appearance, titanium dioxide, FDC dyes) tensile stregth of the film)  Sweetener, flavor and aroma  Remedy: adjusting the plasticizer type and concentration; pigment type and concentration.  Glossant (provide luster without separate pollshing operation) Flaking  Volatile solvent (rapid evaporation)  Film flakes off exposing the tablet surface Typical excipients (Aqueous Film Coating):  Cause: Associated with cracking and splitting  Film former (smooth thin films, cellulose ether  Remedy: adjust spray rate and drying temperature polymers) Infilling  Plasticizer (produce flexibility and elasticity to the coat, glycerin, PEG)  Intagilation filled with either particles of dried  Opacifier and colorant (enhance appearance, polymer or solidified foam titanium dioxide, FDC dyes, lakes, iron oxides)  Cause: bubble or foam formation because of air  Vehicle (water) spraying of polymer solution. Over drying or excessive foaming of coating solution Problems in Film Coating  Remedy: add alcohol or use spray nozzle capable of 1. Blistering finer atomization 2. Wrinkling Orange Peel/Roughness 3. Bridging 4. Sweating  Surface appears similar to that of an orange or 5. Orange-peel lemon 6. Flaking  Cause: poor spreading or spreading of spray 1. Picking-small amounts droplets associated with non-optimum spray 2. Peeling-large amounts atomization 7. Bloom  Remedy: thinning the solution with additional 8. Spotting solvent; use mild drying conditions 9. Erosion (disfiguration) Peeling 10. Twinning 11. Flaking  Film peels off exposing the best tablet surface 12. Infilling  Cause: associated with cracking and splitting 13. Splitting  Remedy: adjust molecular grade of polymer, 14. Cracking balance spray and drying rate 15. Chipping 16. Mottling Splitting 17. Capping  Film splits usually around the edges of the tablet 18. Lamination  Cause: high internal stress in film Blooming  Remedy: use lower molecular weight polymers or polymeric blends and or adjust plasticizer type and  Coating becomes dull immediately after prolong concentration storage. Film becomes detached from substrate forming a blister. Capping and Lamination  Capping is partial or complete separation of top or bottom crowns of tablet main body  Lamination is separation of a tablet into two or more distinct layers  Cause: The problem stems from improper tablet compression, How you operate the coating system,  The coated formulations are tamper evident and however, can exacerbate the problem. can be designed with different colors for branding  Remedy: Be careful not to over-dry the tablets in purposes the preheating stage. That can make the tablets  They are reported to be preferred by patients due brittle and promote capping. to their ease of swallowing and superior taste - and odor- masking properties. Twinning Process of Tablet Coating  This is the term for two tablets that stick together, and it's a common problem with capsule shaped 1. Pan Coating tablets. 2. Dip Coating  REMEDY: balancing the pan speed and spray rate. 3. Compression Coating 4. Air suspension Coating Mottling Requirements of Tablet to be Coated  This can happen when the coating solution is improperly prepared, the actual spray rate differs 1. Optimum convexity from the target rate, the tablet cores are cold, or 2. Sufficient hardness the drying rate is out of specification. 3. Minimal friability 4. Rapid disintegration Bridging 5. Dust-free  coating fills in the lettering or logo on the tablet Functional Coatings  Cause: typically caused by improper application of 1. Enteric the solution 1. Designed to resist dissolution in the  poor design of the tablet embossing high coating stomach but dissolve in the less acid viscosity environment of the intestine (pH 4.8 or  high percentage of solids in the solution greater)  improper atomization pressure 2. Shellac, hydroxypropylmethylcellulose  REMEDY: Increasing the plasticizer content or phthalate changing the plasticizer can decrease the incidence 2. Modified Release of bridging. a) Extended Release Categories of Tablet Coating - FDA: allows reduction in dosing frequency to that presented by a conventional dosage form 1. Sugar-coating b) Delayed Release 2. Compression coating - Aimed at release of drug from the dosage 3. Film-coating form at a time other than promptly after 4. Tablet wrapping or Enrobing administration Tablet Wrapping or Enrobing - Delay may be: » Time based  Recent innovations in tablet coating » pH based  use of gelatin and non-animal-derived coatings for tablets  require formulation of a pre-formed film that is then used to encapsulate the product (e.g., Banner's Soft Gelcaps or Bioprogress 'Nrobe technology) LIQUID DOSAGE FORM Co-solvents - Water miscible solvent in which the drug has good Solutions solubility - Used in combination to increase solubility of solute  two or more substances mixed homogeneously Improve solubility of volatile constituents such as flavor  MOST COMMON liquid dosage form and odor Question? - Ethanol, sorbitol, glycerin, PG, PEG polymer What Type of Water should we use for manufacturing solutions? Solubilizers Aqueous Solvents Use of surfactants to form colloidal aggregates (micelles) USP Waters Polyoxyethylene, fatty acid esters (tween series) Purified Water for Sterile water Bacteriostatic Buffers/pH adjusters/acidifiers water injection for injection water for injection pH selection for solubility and stability Distillation Purified Sterilized Sterile water Salty taste: enhanced by acidifying agents Reverse water that is water for for injection Most commonly used for oral preparations: pH4-7 osmosis PYROGEN injection with Citric, glutaric, lactic acid lon-exchange FREE bacteriostatic Packed in agents Preservatives Used for all single dose types of containers Single or Effective against a broad spectrum of microorganisms, preparation multiple oxidation and hydrolysis EXCEPT Dose Non toxic and non sensitizing irrigation, containers parenterals, Preservatives Classification ophthalmic Acidic Neutral Mercurial Quaternary Selection of Solvent: Ammonium  Clarity Compounds  Low toxicity Phenol Chlorobutanol Thimerosal Benzalkonium Alkyl esters of Benzyl alcohol chloride  Viscosity parahydroxyb  Compatibility with other ingredients enzoic acid  Chemical inertness Benzoic acid  Palatablity and its salts  Color Sweetening Agents  Odor  Economy Combination of sucrose and synthetic sweetener  Decrease caplocking TABLE 1 Solutions: pharmaceutical excipients Aspartame  Synergistic with saccharin, sucrose and glucose Purpose Agent Sorbitol Protecting the active product - Buffers  Mouthfeel ingredients - Antioxidants Artificial sweeteners: > Mixing >> Storage/Aging >> Filtration >> Filling >> Packaging Mixing The random distribution, into and through, one another of two or more initially separate phases Uniformity in composition Promote physical or chemical reactions Mixing Tanks Liquids are most often agitated in a mixing vessel, usually cylindrical in form with a vertical axis. FLUID FLOW PATTERNS Vortex Formation Radial 1. Impeller in an angular off-center position Perpendicular to the impeller shaft Mount the impeller away from the center of the vessel & tilted in the direction perpendicular to the direction of flow. 2. Baffles Longitudinal/Axial What are baffles? Parallel to the impeller shaft 2. Baffles on tank walls are vertical plates (typically about 10% of the tank diameter) that stick out radially from the tank wall. Impede rotational/tangential flow without interfering Tangential with radial or longitudinal flow. Circular path around the shaft 5. Impeller Types Favored by laminar flow Liquid products are most commonly mixed by impellers rotating in tanks. Paddle Description: Flat blades attached to a vertical shaft Speed: Low speed (10-100 rpm) Advantage: No vortex formation (Low speed) Disadvantage Poor mixing of suspension Use: Will depend on the type of paddle used, but most useful in Viscous liquids or semi- solids Propeller Description: With propeller blades that serves as axial thrust-giving elements Speed: High speed (400-1500 rpm) Advantage: Shorter mixing time Disadvantage Not effective with liquids of viscosity greater than 5 Pa Use: commonly used for mixing miscible and immiscible liquids of low viscosity. Turbine Description: Circular disc impeller with short, straight or curved blades attached Speed: Intermediate Advantage: High shearing force Use: Emulsion, High viscosity (7 Pa) and High volume